High susceptibility for cystic fibrosis human airway gland cells to produce IL-8 through the I kappa B kinase alpha pathway in response to extracellular NaCl content

Increasing evidence suggests that in airways from cystic fibrosis (CP) pati ents, inflammation may precede bacterial infection and be related to an end ogenous dysregulation of proinflammatory cytokines in airway epithelial cel ls. Several investigators have reported that, in CF airway fluids, elevated NaCl concentrations may also contribute to the diseased state by inhibitin g the bactericidal properties of airway fluid. Because many proinflammatory cytokines are transcriptionally regulated by the NF-kappa B, we investigat ed whether an elevated extracellular NaCl content in airway fluids signific antly impaired the regulation of the NF-kappa B/I kappa B alpha complex and the chemokine IL-8 production in primary non-CP and CF human bronchial gla nd epithelial cells. Exposure of non-CF gland cells to hypotonic (85 mM) Na Cl solution, compared with isotonic (115 mM) NaCl and hypertonic (170 mM) N aCl solutions, resulted in a significant decrease in IL-8 production that w as paralleled hy a strong inhibition of activated NF-kappa B associated wit h an increased cytosolic expression of I kappa B alpha and a decrease in th e I kappa B kinase alpha protein level, In CF gland cells, we demonstrated that, compared with the high IL-8 in an hypertonic solution, the release of IL-8 was significantly reduced 2-fold in an isotonic solution and 5-fold i n a hypotonic solution. Strikingly, exposure of CF bronchial gland cells to either hypotonic or isotonic milieu did not result in a marked inhibition of the activated NF-kappa B/I kappa B alpha system. This is the first demon stration that primary human CF bronchial gland cells exhibit abnormally hig h IL-8 production through constitutively activated NF-kappa B and high I ka ppa B kinase alpha level, whatever the hypo-, iso-, and hypertonic NaCl mil ieu.